CLINICAL USE OF INHALED ANTICANCER AGENTS
Several attempts have been made to selectively activate local immunity in the lungs to control metastases. Inhaled IL-2 alone given for treatment of patients with renal cancer and NSCLC did not produce impressive results but was more effective when combined with systemic low-dose IL-2 and IFN-a, high-dose systemic IL-2, or chemotherapy (Huland et al. 2000). In patients with metastatic melanoma, aerosol delivery of GM-CSF has modest clinical effects, but it may induce melanoma-specific immunity. The use of inhaled monoclonal antibodies, such as cetuximab, merits further study because they retain activity after aerosolization and are able to penetrate into orthotopic lung tumors in BALB/c nude mice.
The efficacy of inhaled chemotherapy in a clinical setting has been reported by a few investigators (Table 5.1). Inhaled 5-FU achieved tumor tissue levels that were 5-15-fold higher than those in normal lung; the levels were higher than those needed for antineoplastic activity, and 5-FU alone or in combination with other chemotherapy agents was partially effective in patients with NSCLC (Tatsumura et al. 1993). Partial responses in lung tumors and liver metastasis were observed in patients with pulmonary metastasis from a variety of tumors who received inhaled liposomal 9-NC (Vershraegen et al. 2004). A liposomal formulation of cisplatin (SLIT) given over 1-4 consecutive days in 21-day treatment cycles to patients with lung cancer stabilized the disease in 12 out of 17 patients and was not associated with systemic side effects (Wittgen et al. 2007). In 11 patients with NSCLC (including 6 patients with diffuse bronchoalveolar carcinoma) who were unresponsive to previous chemotherapy, weekly inhalation of GEM (0.5 or 1 mg/kg) produced a minor response in one patient and stable disease in 4 patients (Lemarie et al. 2011). Likewise, survival benefit was shown in NSCLC patients after use of inhaled carboplatin in addition to systemic carboplatin in combination with IV docetaxel (Zarogoulidis et al. 2012). In early-stage (stage II) NSCLC patients who received inhaled cisplatin 2 h prior to surgery, the subcarinal lymph node had higher concentrations of cisplatin than those in the blood (Zarogoulidis et al. 2013). Thus, inhaled drugs could diffuse from the alveoli into the lymphatic circulation and regional lymph nodes. Whether inhaled drugs could achieve adequate concentration to lyse cancer cells within lymph nodes needs further evaluation.
In patients with metastatic osteosarcoma limited to the lungs, inhalation of liposomal cisplatin produced sustained benefit in some patients with less bulky disease without producing toxic effects that are commonly observed after IV cisplatin administration (Chou et al. 2013).
There has been much progress in developing vectors for gene delivery and several experimental approaches have been employed, but these approaches have not yet been effectively applied in clinical practice. Replacement of a mutated or absent tumor suppressor gene should lead to suppression of tumor growth or tumor cell death. Several early-phase clinical trials have evaluated restoration of wild-type p53 in lung tumor cells. These approaches have employed direct intratumoral injection with adenoviral vectors and have shown partial responses, but the benefits over chemotherapy or radiotherapy alone have not been convincingly demonstrated in these trials. Promising gene therapy approaches involve stimulation of an endogenous immune response to the tumor and combining antisense therapy with chemotherapy (Taratula et al. 2013).